Safety Profile of Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method (rAHF-PFM) from Post-Authorization Safety Surveillance (PASS) Program.

ADVATE rAHF-PFM was licensed by the FDA in 2003 and the EMEA in 2004 based on studies of previously treated patients (PTPs) with FVIII levels ≤2%. Subsequent to licensure, a PASS program was launched to document rAHF-PFM experience during the first year of routine therapy in subjects with FVIII baseline levels ≤5%, irrespective of prior FVIII exposure or inhibitor history. As of May 25, 2007, a total of 537 subjects (519 male, 2 female, 16 unreported) were enrolled. Of these 537 subjects, 67 were previously untreated or minimally treated patients (PUPs/MTPs) (≤50 exposure days [EDs]), 444 PTPs (>50 EDs), and 26 subjects had an unknown prior exposure status at study entry. Furthermore, 451 had FVIII ≤2%, 62 FVIII >2% to ≤5%, 5 FVIII >5%, 19 unreported. At enrollment, 421 reported switching from recombinant FVIII therapies (343 first generation FL-rFVIII, 38 second generation FL-rFVIII, and 12 BDD-rFVIII), and 76 from plasma-derived-FVIII (34 VWF-containing pdFVIII). Sixty-four subjects had a history of an inhibitor; 33 underwent immune tolerance induction (ITI). Age cohorts were as follows: 0–2 years (n=29), 2–16 years (n=184), and ≥16 years (n=297); 27 were unreported. A total of 417 subjects completed the one-year observation period; 42 withdrew. Twenty AEs were judged at least possibly related to rAHF-PFM; 11 (mostly inhibitors) were rated as serious. Among 387 PTPs with baseline FVIII ≤2%, 2 recurrent, low-titer (1.4 BU and 1.5 BU) and 1 de novo, low-titer (1.4 BU) inhibitors were reported, providing an interim inhibitor risk estimate of 0.78% (95% CI: 0.16–2.25%). In the remaining PTPs, 1 de novo, high-titer (23 BU) inhibitor was reported in a 60-year-old man (FVIII >5%) following surgery, and 1 de novo, low-titer (4 BU) inhibitor, which disappeared 12 months later, developed in a 4-year-old boy (baseline FVIII=5%). Two high-titer inhibitors were reported in PUPs; 1 successfully eradicated with 5 weeks of ITI using rAHF-PFM (100 IU/kg QD). Other related serious AEs included 2 allergic reactions, 1 ineffective drug response in a subject with an inhibitor and ITI history, and 1 hemarthrosis secondary to trauma. Overall, 2771 new bleeds were recorded. Annual bleed rates were 4.3 and 8.3 among subjects on prophylactic and on-demand therapy, respectively. Of 259 subjects with physician-rated prophylaxis efficacy, 91% had only excellent/good ratings. Of 369 subjects with physician-rated bleed treatment efficacy, 94% had only excellent/good ratings. Ratings were comparable among subjects with an inhibitor history. Interim PASS results indicate rAHF-PFM is safe and effective in the management of hemophilia A patients, including those typically excluded from controlled clinical trials.